RESUMO
Organic dye-based agents with near-infrared (NIR)-II absorption have great potential for cancer theranostics because of the deeper tissue penetration and good biocompatibility. However, proper design is required to develop NIR-II-absorbing dyes with good optical properties. We proposed to construct chalcogen atom-modulated croconaine for NIR-II light-triggered photothermal theranostics. By introducing different chalcogen atoms (O, S, Se, or Te) into the structure of croconaine, the light absorption of croconaine can be precisely regulated from the NIR-I to the NIR-II range due to the heavy-atom effect. Especially, Te-substituted croconaine (CRTe) and its nanoformulations exhibit superior NIR-II responsiveness, a high photothermal conversion efficiency (70.6%), and good photostability. With their favorable tumor accumulation, CRTe-NPs from tumor regions can be visualized by NIR-II optoacoustic systems with high resolution and high contrast; meanwhile, their superior photothermal performance also contributes to efficient cell killing and tumor elimination upon 1064 nm laser irradiation. Therefore, this work provides an efficient strategy for the molecular design of NIR-II organic photothermal agents.
Assuntos
Calcogênios , Nanopartículas , Neoplasias , Humanos , Nanomedicina Teranóstica , Neoplasias/tratamento farmacológico , Corantes/química , Calcogênios/farmacologia , Nanopartículas/química , Fototerapia , Linhagem Celular TumoralRESUMO
Selenium is an underexplored element that can be used for bioisosteric replacement of lower molecular weight chalcogens such as oxygen and sulfur. More studies regarding the impact of selenium substitution in different chemical scaffolds are needed to fully grasp this element's potential. Herein, we decided to evaluate the impact of selenium incorporation in a series of tryptophan 2,3-dioxygenase (TDO2) inhibitors, a target of interest in cancer immunotherapy. First, we synthesized the different chalcogen isosteres through Suzuki-Miyaura type coupling. Next, we evaluated the isosteres' affinity and selectivity for TDO2, as well as their lipophilicity, microsomal stability and cellular toxicity on TDO2-expressing cell lines. Overall, chalcogen isosteric replacements did not disturb the on-target activity but allowed for a modulation of the compounds' lipophilicity, toxicity and stability profiles. The present work contributes to our understanding of oxygen/sulfur/selenium isostery towards increasing structural options in medicinal chemistry for the development of novel and distinctive drug candidates.
Assuntos
Calcogênios/farmacologia , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos/farmacologia , Selênio/farmacologia , Triptofano Oxigenase/antagonistas & inibidores , Calcogênios/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Estrutura Molecular , Oxigênio/química , Oxigênio/farmacologia , Selênio/química , Estereoisomerismo , Relação Estrutura-Atividade , Enxofre/química , Enxofre/farmacologia , Triptofano Oxigenase/metabolismoRESUMO
Most of the existing single-component nanostructures cannot provide comprehensive diagnostic information, and their treatment strategies always have to combine other therapeutics as a complementary for effective biomedical application. Here, we adopted a facile approach to design a theranostic nanoflower (NF) with robust efficacy for comprehensive tumor diagnosis and quadruple synergistic cancer therapy. The NF is equipped with a metallic hybrid of several functional elements and flower-like superstructures and thus shows excellent in vitro and in vivo theranostic performance. It shows high X-ray attenuation coefficiency for the Bi element, strong near-infrared (NIR) plasmon absorbance and singlet oxygen (1O2) generation ability for the Mo element, and great photothermal conversion efficiency (54.7%) because of enhanced photoabsorption of the petal structure. Moreover, the NF realizes a very high doxorubicin-loading efficiency (90.0%) and bimodal pH/NIR-responsive drug release, posing a promise as a controlled drug carrier. The NF also shows excellent performance at trimodal magnetic resonance/X-ray computed tomography/photoacoustic imaging for comprehensive tumor diagnosis. To our best knowledge, it is the first time that integrating at least seven functions into one biomedical nanomaterial for well-rounded tumor theranostics has been reported. This "all-in-one" NF opens a new perspective in developing novel and efficient multifunctional nanotheranostics.
Assuntos
Doxorrubicina/farmacologia , Portadores de Fármacos/farmacologia , Neoplasias/tratamento farmacológico , Nanomedicina Teranóstica , Animais , Bismuto/química , Calcogênios/química , Calcogênios/farmacologia , Terapia Combinada , Cobre/química , Doxorrubicina/química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Células HeLa , Humanos , Camundongos , Nanoestruturas/química , Neoplasias/diagnóstico por imagem , Neoplasias/radioterapia , Técnicas Fotoacústicas/métodos , Fotoquimioterapia/métodos , Oxigênio Singlete/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Selenium is traditionally considered as an antioxidant element and selenium compounds are often discussed in the context of chemoprevention and therapy. Recent studies, however, have revealed a rather more colorful and diverse biological action of selenium-based compounds, including the modulation of the intracellular redox homeostasis and an often selective interference with regulatory cellular pathways. Our basic activity and mode of action studies with simple selenium and tellurium salts in different strains of Staphylococcus aureus (MRSA) and Saccharomyces cerevisiae indicate that such compounds are sometimes not particularly toxic on their own, yet enhance the antibacterial potential of known antibiotics, possibly via the bioreductive formation of insoluble elemental deposits. Whilst the selenium and tellurium compounds tested do not necessarily act via the generation of Reactive Oxygen Species (ROS), they seem to interfere with various cellular pathways, including a possible inhibition of the proteasome and hindrance of DNA repair. Here, organic selenides are considerably more active compared to simple salts. The interference of selenium (and tellurium) compounds with multiple targets could provide new avenues for the development of effective antibiotic and anticancer agents which may go well beyond the traditional notion of selenium as a simple antioxidant.
Assuntos
Desenho de Fármacos , Compostos Organosselênicos/farmacologia , Sais/farmacologia , Selênio/farmacologia , Telúrio/farmacologia , Anti-Infecciosos/farmacologia , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Calcogênios/farmacologia , Testes de Sensibilidade Microbiana , Compostos Organosselênicos/química , Oxirredução , Inibidores de Proteassoma/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Saccharomyces cerevisiae/efeitos dos fármacos , Selênio/química , Staphylococcus aureus/citologia , Staphylococcus aureus/efeitos dos fármacosRESUMO
Microbial metabolism of inorganics has been the subject of interest since the 1970s when it was recognized that bacteria are involved in the transformation of metal compounds in the environment. This area of research is generally referred to as bioinorganic chemistry or microbial biogeochemistry. Here, we overview the way the chalcogen metalloids Se and Te interact with bacteria. As a topic of considerable interest for basic and applied research, bacterial processing of tellurium and selenium oxyanions has been reviewed a few times over the past 15 years. Oddly, this is the first time these compounds have been considered together and their similarities and differences highlighted. Another aspect touched on for the first time by this review is the bacterial response in cell-cell or cell-surface aggregates (biofilms) against the metalloid oxyanions. Finally, in this review we have attempted to rationalize the considerable amount of literature available on bacterial resistance to the toxic metalloids tellurite and selenite.
Assuntos
Bactérias/metabolismo , Calcogênios/metabolismo , Selênio/metabolismo , Telúrio/metabolismo , Bactérias/efeitos dos fármacos , Biofilmes , Calcogênios/farmacologia , Selênio/farmacologia , Telúrio/farmacologiaRESUMO
A series of fluorinated diphenylchalcogen derivatives, possessing a sulfur or an oxygen bridge, has been prepared with the aim to get a suitable radiotracer to image the SERT in vivo using positron emission tomography (PET). The compounds were synthesized and assayed toward the serotonin (SERT), dopamine (DAT), and norepinephrine (NET) transporters. Among the developed series, five compounds display a high SERT affinity (K(i): 0.27-2.91 nM range) and can be labeled either with carbon-11 or fluorine-18.
Assuntos
Calcogênios/síntese química , Química Farmacêutica/métodos , Hidrocarbonetos Fluorados/síntese química , Tomografia por Emissão de Pósitrons/métodos , Proteínas da Membrana Plasmática de Transporte de Serotonina/química , Animais , Encéfalo/efeitos dos fármacos , Calcogênios/química , Calcogênios/farmacologia , Dopamina/metabolismo , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/farmacologia , Modelos Químicos , Norepinefrina/metabolismo , Ratos , Serotonina/metabolismo , Transdução de SinaisRESUMO
Tumor cells proliferate under conditions of oxidative stress. A novel therapeutic approach would be to enhance the cellular effects of the reactive oxygen species formed under these conditions by supplementation with a redox catalyst. This provides a means to target and specifically destroy cancer cells via oxidation of redox-sensitive proteins, such as transcription factors, while leaving cells with a normal redox balance largely unaffected. We have previously reported a preliminary observation on the effects of pro-oxidant catalysts that enhance cancer cell death. This paper presents a detailed in vitro investigation into the mechanism of action of synthetic glutathione peroxidase mimics on a model Sp1 transcription factor peptide. The structure and redox potential of these mimics correlate with their ability to catalyze the oxidation of this zinc-binding motif by H(2)O(2) and these compounds promise therapeutic potential by promoting H(2)O(2)-induced PC12 cell death.